Re-evaluation of some popular CRAC channel inhibitors – structurally similar but mechanistically different?

Ca ²⁺ -release activated Ca ²⁺ (CRAC) channels mediate the store-operated Ca ²⁺ entry (SOCE) that is used almost by all cells to replenish depleted intracellular Ca ²⁺ stores. Aberrant CRAC channel functions have been implicated in various diseases including autoimmune diseases and as such these channels and the resultant pathway (SOCE) have been intensively studied by academic and pharmaceutical scientists over decades. To date, several small molecule inhibitors and few antibodies have been developed against these ion channels. Some small molecule inhibitors of the CRAC channels, namely BTP2, Synta66, Pyr6 and GSK-7975A, are widely used as tool compounds in the field but their mode of action remains unclear. In this study, we used whole cell electrophysiology supported by in silico modelling to propose likely binding site and binding mode of these four popular CRAC channel inhibitors.